Epidemic influenza A is an emerging public health problem for both humans and domestic animals. In the last 10 years, human influenza has caused severe morbidity among US domestic swine, herds, avian influenza has caused the destruction of large poultry flocks in Virginia and North Carolina, and avian influenza has caused unusual human disease or deaths in Hong Kong, the Netherlands, Belgium, and likely the Eastern United States. We plan to initiate a series of epidemiological studies of zoonotic influenza A with a long term goal of reducing cross-species influenza morbidity. Our objective in this first application is to prospectively determine risk factors and the incidence of zoonotic influenza infection among rural mid-western agricultural workers. It is our central hypothesis that zoonotic influenza infection will be relatively frequent among Iowan swine and poultry workers and that we will be able to identify populations at high risk as well as estimate the incidence of infection among various populations. We will use data from the 90,000-person Agricultural Health Study (AHS) to identify study subjects who are occupationally exposed to swine (n=200), poultry (n=200), swine and poultry (n=200) and a gender and age-matched (4:1) group of 150 control subjects without such exposures. As influenza activity cannot be predicted we will follow the subjects over two winter periods. Upon enrollment, and after 12 and 24 months of follow-up, participants will be asked to complete a questionnaire and donate sera. If participants develop signs and symptoms of an influenza-like illness, they will additionally be asked to complete a questionnaire, and to permit the collection of a throat swab, a posterior nasal swab, and a gargle sample within 48 hours of symptom development. Laboratory studies will be performed on sera samples to detect infection with swine and avian influenza virus types. Molecular studies and culture will be used to additionally identify influenza strains from the swab and gargle samples. We are particularly well suited to conduct this work as we have extensive experience conducting both epidemiological and laboratory-based studies of respiratory pathogens.